Pharmacological interactions between calcium/calmodulin-dependent kinase II alpha and TRPV1 receptors in rat trigeminal sensory neurons.

Multiple lines of evidence suggest that calcium/calmodulin-dependent kinase II alpha (CaMKIIalpha) plays an important role in the spinal dorsal horn in nociceptive models of chemical, inflammatory and nerve injury. Moreover, CaMKIIalpha phosphorylates the vanilloid receptor type 1 (TRPV1), thereby regulating vanilloid agonist binding to the receptor. Herein, we have explored a possible interaction of CaMKIIalpha activity with the TRPV1 receptor in rat trigeminal ganglion (TG) neurons in vitro. Inhibition of CaMKIIalpha with KN-93 (5 microM) inhibited capsaicin (CAP)- and n-arachidonoyl-dopamine (NADA)-evoked calcitonin gene-related peptide (CGRP) release effectively decreasing the Emax for both compounds. This effect was not mimicked by the inactive compound KN-92 (5 microM), indicating that the effect was mediated by CaMKIIalpha inhibition. CAP also stimulated a significant approximately 50% increase in autophosphorylation of CaMKIIalpha at Thr286/287. Immunocytochemistry for phospho-CaMKIIalpha indicated that this effect specifically occurred in TRPV1-positive TG neurons. These findings indicate that phopho-CaMKIIalpha is likely to play a role in presynaptic primary afferents in animal models of nociceptive hypersensitivity and provide support for CaMKIIalpha modulation of TRPV1 activity in sensory neurons.